Deep-sequencing of viral genomes from a large and diverse cohort of treatment-naive HIV-infected persons shows associations between intrahost genetic diversity and viral load.

BACKGROUND: Infection with human immunodeficiency virus type 1 (HIV) typically results from transmission of a small and genetically uniform viral population. Following transmission, the virus population becomes more diverse because of recombination and acquired mutations through genetic drift and selection. Viral intrahost genetic diversity remains a major obstacle to the cure of HIV; however, the association between intrahost diversity and disease progression markers has not been investigated in large and diverse cohorts for which the majority of the genome has been deep-sequenced. Viral load (VL) is a key progression marker and understanding of its relationship to viral intrahost genetic diversity could help design future strategies for HIV monitoring and treatment. METHODS: We analysed deep-sequenced viral genomes from 2,650 treatment-naive HIV-infected persons to measure the intrahost genetic diversity of 2,447 genomic codon positions as calculated by Shannon entropy. We tested for associations between VL and amino acid (AA) entropy accounting for sex, age, race, duration of infection, and HIV population structure. RESULTS: We confirmed that the intrahost genetic diversity is highest in the env gene. Furthermore, we showed that mean Shannon entropy is significantly associated with VL, especially in infections of >24 months duration. We identified 16 significant associations between VL (p-value<2.0x10-5) and Shannon entropy at AA positions which in our association analysis explained 13% of the variance in VL. Finally, equivalent analysis based on variation in HIV consensus sequences explained only 2% of VL variance. CONCLUSIONS: Our results elucidate that viral intrahost genetic diversity is associated with VL and could be used as a better disease progression marker than HIV consensus sequence variants, especially in infections of longer duration. We emphasize that viral intrahost diversity should be considered when studying viral genomes and infection outcomes. TRIAL REGISTRATION: Samples included in this study were derived from participants who consented in the clinical trial, START (NCT00867048) (23), run by the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT). All the participant sites are listed here: http://www.insight-trials.org/start/my_phpscript/participating.php?by=site.

Understanding the Decline of Incident, Active Tuberculosis in People With Human Immunodeficiency Virus in Switzerland.

BACKGROUND: People with human immunodeficiency virus type 1 (HIV-1) (PWH) are frequently coinfected with Mycobacterium tuberculosis (MTB) and at risk for progressing from asymptomatic latent TB infection (LTBI) to active tuberculosis (TB). LTBI testing and preventive treatment (TB specific prevention) are recommended, but its efficacy in low transmission settings is unclear. METHODS: We included PWH enrolled from 1988 to 2022 in the Swiss HIV Cohort study (SHCS). The outcome, incident TB, was defined as TB ≥6 months after SHCS inclusion. We assessed its risk factors using a time-updated hazard regression, modeled the potential impact of modifiable factors on TB incidence, performed mediation analysis to assess underlying causes of time trends, and evaluated preventive measures. RESULTS: In 21 528 PWH, LTBI prevalence declined from 15.1% in 2001% to 4.6% in 2021. Incident TB declined from 90.8 cases/1000 person-years in 1989 to 0.1 in 2021. A positive LTBI test showed a higher risk for incident TB (hazard ratio [HR] 9.8, 5.8-16.5) but only 10.5% of PWH with incident TB were tested positive. Preventive treatment reduced the risk in LTBI test positive PWH for active TB (relative risk reduction, 28.1%, absolute risk reduction 0.9%). On population level, the increase of CD4 T-cells and reduction of HIV viral load were the main driver of TB decrease. CONCLUSIONS: TB specific prevention is effective in selected patient groups. On a population level, control of HIV-1 remains the most important factor for incident TB reduction. Accurate identification of PWH at highest risk for TB is an unmet clinical need.

Early Antiretroviral Therapy Not Associated With Higher Cryptococcal Meningitis Mortality in People With Human Immunodeficiency Virus in High-Income Countries: An International Collaborative Cohort Study.

BACKGROUND: Randomized controlled trials (RCTs) from low- and middle-income settings suggested that early initiation of antiretroviral therapy (ART) leads to higher mortality rates among people with HIV (PWH) who present with cryptococcal meningitis (CM). There is limited information about the impact of ART timing on mortality rates in similar people in high-income settings. METHODS: Data on ART-naive PWH with CM diagnosed from 1994 to 2012 from Europe/North America were pooled from the COHERE, NA-ACCORD, and CNICS HIV cohort collaborations. Follow-up was considered to span from the date of CM diagnosis to earliest of the following: death, last follow-up, or 6 months. We used marginal structural models to mimic an RCT comparing the effects of early (within 14 days of CM) and late (14-56 days after CM) ART on all-cause mortality, adjusting for potential confounders. RESULTS: Of 190 participants identified, 33 (17%) died within 6 months. At CM diagnosis, their median age (interquartile range) was 38 (33-44) years; the median CD4+ T-cell count, 19/µL (10-56/µL); and median HIV viral load, 5.3 (4.9-5.6) log10 copies/mL. Most participants (n = 157 [83%]) were male, and 145 (76%) started ART. Mimicking an RCT, with 190 people in each group, there were 13 deaths among participants with an early ART regimen and 20 deaths among those with a late ART regimen. The crude and adjusted hazard ratios comparing late with early ART were 1.28 (95% confidence interval, .64-2.56) and 1.40 (.66-2.95), respectively. CONCLUSIONS: We found little evidence that early ART was associated with higher mortality rates among PWH presenting with CM in high-income settings, although confidence intervals were wide.

Prevalence of STIs and people's satisfaction in a general population STI testing site in Bern, Switzerland.

OBJECTIVES: Access to affordable STI testing for asymptomatic persons is important to reduce STI transmission. Our testing site offers easily accessible and affordable STI testing for the general population irrespective of symptoms. Here we report STI prevalence and motivational factors of attendance. METHODS: Between 2017 and 2019, all participants at our STI testing site at the University Hospital Bern, Switzerland, were interviewed with a computer-based self-completion questionnaire. Pooled (oral, genital and anal) swabs were tested for Chlamydia trachomatis, Neisseria gonorrhoeae and blood samples for syphilis and HIV. People's motivational factors to attend were assessed using a standardised questionnaire. RESULTS: 5402 individuals between 17 and 82 (median 33.5) years were included. Of those, 2550 (47.2%) were between 25 and 34 years old and 3133 were heterosexual (58%), with rising attendance over the years. One-third attended because of a new sexual relationship, and one-third reported condomless sex. Among all individuals, we found 191 (3.8%) new chlamydia infections (89/191 in females and 101/191 in males) and 54 (1.1%) gonorrhoea infections (44/54 in males). In addition, 52/5125 tested individuals (0.8%) had syphilis requiring treatment.The number of sexual partners, previous bacterial STIs and condomless sex were associated with having an STI. Four heterosexual individuals were newly diagnosed with HIV. People rated a low threshold offer (through online booking or telephone) and personal counselling as most important factors to attend the service. CONCLUSION: We found many asymptomatic bacterial STIs requiring treatment. Offering easily accessible STI testing and counselling proved successful as shown by increasing rates of attendance and high levels of satisfaction.

Diagnosis of latent tuberculosis infection is associated with reduced HIV viral load and lower risk for opportunistic infections in people living with HIV.

Approximately 28% of the human population have been exposed to Mycobacterium tuberculosis (MTB), with the overwhelming majority of infected individuals not developing disease (latent TB infection (LTBI)). While it is known that uncontrolled HIV infection is a major risk factor for the development of TB, the effect of underlying LTBI on HIV disease progression is less well characterized, in part because longitudinal data are lacking. We sorted all participants of the Swiss HIV Cohort Study (SHCS) with at least 1 documented MTB test into one of the 3 groups: MTB uninfected, LTBI, or active TB. To detect differences in the HIV set point viral load (SPVL), linear regression was used; the frequency of the most common opportunistic infections (OIs) in the SHCS between MTB uninfected patients, patients with LTBI, and patients with active TB were compared using logistic regression and time-to-event analyses. In adjusted models, we corrected for baseline demographic characteristics, i.e., HIV transmission risk group and gender, geographic region, year of HIV diagnosis, and CD4 nadir. A total of 13,943 SHCS patients had at least 1 MTB test documented, of whom 840 (6.0%) had LTBI and 770 (5.5%) developed active TB. Compared to MTB uninfected patients, LTBI was associated with a 0.24 decreased log HIV SPVL in the adjusted model (p < 0.0001). Patients with LTBI had lower odds of having candida stomatitis (adjusted odds ratio (OR) = 0.68, p = 0.0035) and oral hairy leukoplakia (adjusted OR = 0.67, p = 0.033) when compared to MTB uninfected patients. The association of LTBI with a reduced HIV set point virus load and fewer unrelated infections in HIV/TB coinfected patients suggests a more complex interaction between LTBI and HIV than previously assumed.

Impact of Latent Tuberculosis on Diabetes.

While an increased risk of active and latent tuberculosis infection (LTBI) in people with type-2 diabetes (DM) has been demonstrated, it is less well characterized whether LTBI is associated with an increased risk of developing DM. We investigated the link between LTBI and DM in people living with HIV in the Swiss HIV Cohort Study via time-dependent Cox proportional hazards models. We found that LTBI significantly increased the risk of developing DM (HR = 1.47), which was robust across different adjustment and censoring techniques. Our results thus suggest that LTBI may be associated with an increased risk of developing DM.

Decreasing Incidence and Determinants of Bacterial Pneumonia in People With HIV: The Swiss HIV Cohort Study.

BACKGROUND: Bacterial pneumonia is a leading reason for hospitalization among people with HIV (PWH); however, evidence regarding its drivers in the era of potent antiretroviral therapy is limited. METHODS: We assessed risk factors for bacterial pneumonia in the Swiss HIV Cohort Study using marginal models. We further assessed the relationship between risk factors and changes in bacterial pneumonia incidence using mediation analysis. RESULTS: We included 12927 PWH with follow-ups between 2008 and 2018. These patients had 985 bacterial pneumonia events during a follow-up of 100779 person-years. Bacterial pneumonia incidence significantly decreased from 13.2 cases/1000 person-years in 2008 to 6.8 cases/1000 person-years in 2018. Older age, lower education level, intravenous drug use, smoking, lower CD4-cell count, higher HIV load, and prior pneumonia were significantly associated with higher bacterial pneumonia incidence. Notably, CD4 cell counts 350-499 cells/µL were significantly associated with an increased risk compared to CD4 ≥ 500 cells/µL (adjusted hazard ratio, 1.39; 95% confidence interval, 1.01-1.89). Decreasing incidence over the last decade can be explained by increased CD4-cell counts and viral suppression and decreased smoking frequency. CONCLUSIONS: Improvements in cascade of care of HIV and decrease in smoking may have mediated a substantial decrease in bacterial pneumonia incidence.

Increasing Frequency and Transmission of HIV-1 Non-B Subtypes Among Men Who Have Sex With Men in the Swiss HIV Cohort Study.

BACKGROUND: In Switzerland, HIV-1 transmission among men who have sex with men (MSM) has been dominated by subtype B, whilst non-B subtypes are commonly attributed to infections acquired abroad among heterosexuals. Here, we evaluated the temporal trends of non-B subtypes and the characteristics of molecular transmission clusters (MTCs) among MSM. METHODS: Sociodemographic and clinical data and partial pol sequences were obtained from participants enrolled in the Swiss HIV Cohort Study. For non-B subtypes, maximum likelihood trees were constructed, from which Swiss MTCs were identified and analyzed by transmission group. RESULTS: Non-B subtypes were identified in 8.1% (416/5116) of MSM participants. CRF01_AE was the most prevalent strain (3.5%), followed by subtype A (1.2%), F (1.1%), CRF02_AG (1.1%), C (0.9%), and G (0.3%). Between 1990 and 2019, an increase in the proportion of newly diagnosed individuals (0/123 [0%] to 11/32 [34%]) with non-B subtypes in MSM was found. Across all non-B subtypes, the majority of MSM MTCs were European. Larger MTCs were observed for MSM than heterosexuals. CONCLUSIONS: We found a substantial increase in HIV-1 non-B subtypes among MSM in Switzerland and the occurrence of large MTCs, highlighting the importance of molecular surveillance in guiding public health strategies targeting the HIV-1 epidemic.

Weight and Metabolic Changes After Switching From Tenofovir Disoproxil Fumarate to Tenofovir Alafenamide in People Living With HIV : A Cohort Study.

BACKGROUND: Tenofovir-based antiretroviral therapy (ART) has become first-line in all major HIV treatment guidelines. Compared with tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF) has a favorable renal and bone safety profile, but concerns about metabolic complications remain. OBJECTIVE: To assess weight changes, the development of overweight/obesity, and changes in lipid levels 18 months after replacing TDF with TAF. DESIGN: Cohort study. SETTING: 5 university hospitals, affiliated hospitals, and private physicians in Switzerland. PARTICIPANTS: 4375 adults living with HIV who received TDF-containing ART for 6 months or longer. MEASUREMENTS: Changes in weight and lipid levels were assessed using mixed-effect models. Differences in proportions of newly overweight/obese participants were calculated using 2-proportions Z tests. RESULTS: 4375 individuals were included, with follow-up between 1 January 2016 and 31 July 2019. Median age was 50 years (interquartile range, 43 to 56 years), 25.9% were female, and 51.7% had a normal body mass index (BMI); 3484 (79.6%) switched to TAF and 891 (20.4%) continued TDF. After 18 months, switching to TAF was associated with an adjusted mean weight increase of 1.7 kg (95% CI, 1.5 to 2.0 kg), compared with 0.7 kg (CI, 0.4 to 1.0 kg) with the continued use of TDF (between-group difference, 1.1 kg [CI, 0.7 to 1.4 kg]). Among individuals with a normal BMI, 13.8% who switched to TAF became overweight/obese, compared with 8.4% of those continuing TDF (difference, 5.4 percentage points [CI, 2.1 to 8.8 percentage points]). Switching to TAF led to increases in adjusted mean total cholesterol (0.25 mmol/L [9.5 mg/dL]), high-density lipoprotein cholesterol (0.05 mmol/L [1.9 mg/dL]), low-density lipoprotein cholesterol (0.12 mmol/L [4.7 mg/dL]), and triglyceride (0.18 mmol/L [16.1 mg/dL]) levels after 18 months. LIMITATION: Short follow-up, small subgroup analyses, and potential residual confounding. CONCLUSION: Replacing TDF with TAF is associated with adverse metabolic changes, including weight increase, development of obesity, and worsening serum lipid levels. PRIMARY FUNDING SOURCE: Swiss National Science Foundation.

The Role of Human Immunodeficiency Virus (HIV) Asymptomatic Status When Starting Antiretroviral Therapy on Adherence and Treatment Outcomes and Implications for Test and Treat: The Swiss HIV Cohort Study.

BACKGROUND: Since the advent of universal test-and-treat , more people living with human immunodeficiency virus (PLHIV) initiating antiretroviral therapy (ART) are asymptomatic with a preserved immune system. We explored the impact of asymptomatic status on adherence and clinical outcomes. METHODS: PLHIV registered in the Swiss HIV Cohort Study (SHCS) between 2003 and 2018 were included. We defined asymptomatic as Centers for Disease Control and Prevention stage A within 30 days of starting ART, non-adherence as any self-reported missed doses and viral failure as two consecutive viral load>50 copies/mL after >24 weeks on ART. Using logistic regression models, we measured variables associated with asymptomatic status and adherence and Cox proportional hazard models to assess association between symptom status and viral failure. RESULTS: Of 7131 PLHIV, 76% started ART when asymptomatic and 1478 (22%) experienced viral failure after a median of 1.9 years (interquartile range, 1.1-4.2). In multivariable models, asymptomatic PLHIV were more likely to be younger, men who have sex with men, better educated, have unprotected sex, have a HIV-positive partner, have a lower viral load, and have started ART more recently. Asymptomatic status was not associated with nonadherence (odds ratio, 1.03 [95% confidence interval {CI}, .93-1.15]). Asymptomatic PLHIV were at a decreased risk of viral failure (adjusted hazard ratio, 0.87 [95% CI, .76-1.00]) and less likely to develop resistance (14% vs 27%, P < .001) than symptomatic PLHIV. CONCLUSIONS: Despite concerns regarding lack of readiness, our study found no evidence of adherence issues or worse clinical outcomes in asymptomatic PLHIV starting ART.

Predictors of Virological Failure and Time to Viral Suppression of First-Line Integrase Inhibitor-Based Antiretroviral Treatment.

BACKGROUND: Integrase strand transfer inhibitors (InSTIs) are recommended for first-line treatment of persons with human immunodeficiency virus (HIV). We identified risk factors, including baseline minor InSTI resistance mutations, for treatment failure of InSTI-based regimens. METHODS: We studied time-to-treatment failure and time to viral suppression among 1419 drug-naive patients in the Swiss HIV Cohort Study. We performed Cox regression models adjusted for demographic factors, baseline HIV RNA/CD4 cell counts, AIDS-defining events, and the type of InSTI. In 646 patients with a baseline genotypic resistance test of the integrase, we studied the impact of minor integrase resistance mutations. RESULTS: We observed 121 virological failures during 18 447 person-years of follow-up. A baseline viral load ≥100 000 copies/mL (multivariable hazard ratio [mHR], 2.2; 95% confidence interval [CI], 1.3-3.6) and an AIDS-defining event (mHR, 1.8; 95% CI. 1.1-3.0) were associated with treatment failure. CD4 counts between 200 and 500 cells/µL (mHR, 0.5; 95% CI, .3-.8) and >500 cells/µL (mHR, 0.4; 95% CI, .2-.7) were protective. Time to suppression was shorter in lower viral load strata (mHR, 0.7; 95% CI, .6-.8) and in dolutegravir-based therapy (mHR, 1.2; 95% CI, 1.0-1.4). Minor resistance mutations were found at baseline in 104 of 646 (16%) patients with no effect on treatment outcome. CONCLUSIONS: Factors associated with treatment failure on InSTI-based first-line regimen remained similar to those of older treatments, in particular high viral load and low CD4 counts.

Withholding Primary Pneumocystis Pneumonia Prophylaxis in Virologically Suppressed Patients With Human Immunodeficiency Virus: An Emulation of a Pragmatic Trial in COHERE.

BACKGROUND: Using data from the COHERE collaboration, we investigated whether primary prophylaxis for pneumocystis pneumonia (PcP) might be withheld in all patients on antiretroviral therapy (ART) with suppressed plasma human immunodeficiency virus (HIV) RNA (≤400 copies/mL), irrespective of CD4 count. METHODS: We implemented an established causal inference approach whereby observational data are used to emulate a randomized trial. Patients taking PcP prophylaxis were eligible for the emulated trial if their CD4 count was ≤200 cells/µL in line with existing recommendations. We compared the following 2 strategies for stopping prophylaxis: (1) when CD4 count was >200 cells/µL for >3 months or (2) when the patient was virologically suppressed (2 consecutive HIV RNA ≤400 copies/mL). Patients were artificially censored if they did not comply with these stopping rules. We estimated the risk of primary PcP in patients on ART, using the hazard ratio (HR) to compare the stopping strategies by fitting a pooled logistic model, including inverse probability weights to adjust for the selection bias introduced by the artificial censoring. RESULTS: A total of 4813 patients (10 324 person-years) complied with eligibility conditions for the emulated trial. With primary PcP diagnosis as an endpoint, the adjusted HR (aHR) indicated a slightly lower, but not statistically significant, different risk for the strategy based on viral suppression alone compared with the existing guidelines (aHR, .8; 95% confidence interval, .6-1.1; P = .2). CONCLUSIONS: This study suggests that primary PcP prophylaxis might be safely withheld in confirmed virologically suppressed patients on ART, regardless of their CD4 count.

[Sexually transmitted anorectal infections]. / Sexuell übertragbare anorektale Infektionen.

Sexually transmitted anorectal infections Abstract. In recent years, the incidence of sexually transmitted infections in Switzerland has increased significantly for various reasons. They often manifest with anorectal symptoms, and may present as localized lesions, proctitis, or enteritis. To avoid misdiagnosis and stop transmissions to their sexual partners, testing for sexually transmitted diseases is indicated in most individuals with anorectal symptoms. This article provides an overview of the diagnosis and treatment of sexually transmitted anorectal infections.

Changes in Renal Function After Switching From TDF to TAF in HIV-Infected Individuals: A Prospective Cohort Study.

BACKGROUND: Replacing tenofovir disoproxil fumarate (TDF) with tenofovir alafenamide (TAF) improves renal tubular markers in HIV-infected individuals but the impact on estimated glomerular filtration rate (eGFR) remains unclear. METHODS: In all participants from the Swiss HIV Cohort Study who switched from TDF to TAF-containing antiretroviral regimen or continued TDF, we estimated changes in eGFR and urine protein-to-creatinine ratio (UPCR) after 18 months using mixed-effect models. RESULTS: Of 3520 participants (26.6% women, median age 50 years), 2404 (68.5%) switched to TAF. Overall, 1664 (47.3%) had an eGFR <90 mL/min and 1087 (30.9%) an UPCR ≥15 mg/mmol. In patients with baseline eGFR ≥90 mL/min, eGFR decreased with the use of TDF and TAF (-1.7 mL/min). Switching to TAF was associated with increases in eGFR of 1.5 mL/min (95% confidence interval [CI], .5-2.5) if the baseline eGFR was 60-89 mL/min, and 4.1 mL/min (95% CI, 1.6-6.6) if <60 mL/min. In contrast, eGFR decreased by 5.8 mL/min (95% CI, 2.3-9.3) with continued use of TDF in individuals with baseline eGFR <60 mL/min. UPCR decreased after replacing TDF by TAF, independent of baseline eGFR. CONCLUSIONS: Switching from TDF to TAF improves eGFR and proteinuria in patients with renal dysfunction.

Emergence of Drug Resistance in the Swiss HIV Cohort Study Under Potent Antiretroviral Therapy Is Observed in Socially Disadvantaged Patients.

BACKGROUND: The rate of acquired human immunodeficiency virus type 1 (HIV-1) drug resistance (ADR) has fallen dramatically since introduction of combined antiretroviral therapy (cART) in Switzerland. However, clinical experience indicates that there are still patients at risk of newly acquiring drug resistance despite having access to cART. Here, we characterized risk factors for ADR, to improve patient care and prevent emergence of drug resistance and treatment failure. METHODS: We performed a case-control study to identify risk factors for ADR in all patients starting their first cART in the Swiss HIV Cohort Study (SHCS) since 1996. The SHCS is highly representative and includes >75% of patients receiving ART in Switzerland. To this end, we implemented a systematic medical chart review to obtain more detailed information on additional parameters, which are not routinely collected in the SHCS. The collected data were analyzed using univariable and multivariable conditional logistic regression. RESULTS: We included in our study 115 cases and 115 matched controls. Unemployment (multivariable odds ratio [mOR], 2.9 [95% confidence interval {CI}, 1.3-6.4]; P = .008), African origin (mOR, 3.0 [95% CI, 1.0-9.2]; P = .047), comedication with anti-infectives (mOR, 3.7 [95% CI, 1.0-12.6]; P = .045), and symptoms of mental illness (mOR, 2.6 [95% CI, 1.2-5.5]; P = .012) were associated with ADR in the multivariable model. CONCLUSIONS: Although ADR has become very rare with cART due to new potent therapies, patients in socially challenging life situations or presenting with mental health issues are at higher risk for drug resistance. Prompt identification and adequate support of these patients before ADR will prevent treatment failure and HIV-1 transmission.

Contribution of Genetic Background and Data Collection on Adverse Events of Anti-human Immunodeficiency Virus (HIV) Drugs (D:A:D) Clinical Risk Score to Chronic Kidney Disease in Swiss HIV-infected Persons With Normal Baseline Estimated Glomerular Filtration Rate.

BACKGROUND: In human immunodeficiency virus (HIV), the relative contribution of genetic background, clinical risk factors, and antiretrovirals to chronic kidney disease (CKD) is unknown. METHODS: We applied a case-control design and performed genome-wide genotyping in white Swiss HIV Cohort participants with normal baseline estimated glomerular filtration rate (eGFR >90 mL/minute/1.73 m2). Univariable and multivariable CKD odds ratios (ORs) were calculated based on the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) score, which summarizes clinical CKD risk factors, and a polygenic risk score that summarizes genetic information from 86 613 single-nucleotide polymorphisms. RESULTS: We included 743 cases with confirmed eGFR drop to <60 mL/minute/1.73 m2 (n = 144) or ≥25% eGFR drop to <90 mL/minute/1.73 m2 (n = 599), and 322 controls (eGFR drop <15%). Polygenic risk score and D:A:D score contributed to CKD. In multivariable analysis, CKD ORs were 2.13 (95% confidence interval [CI], 1.55-2.97) in participants in the fourth (most unfavorable) vs first (most favorable) genetic score quartile; 1.94 (95% CI, 1.37-2.65) in the fourth vs first D:A:D score quartile; and 2.98 (95% CI, 2.02-4.66), 1.70 (95% CI, 1.29-2.29), and 1.83 (95% CI, 1.45-2.40), per 5 years of exposure to atazanavir/ritonavir, lopinavir/ritonavir, and tenofovir disoproxil fumarate, respectively. Participants in the first genetic score quartile had no increased CKD risk, even if they were in the fourth D:A:D score quartile. CONCLUSIONS: Genetic score increased CKD risk similar to clinical D:A:D score and potentially nephrotoxic antiretrovirals. Irrespective of D:A:D score, individuals with the most favorable genetic background may be protected against CKD.

Emulating a trial of joint dynamic strategies: An application to monitoring and treatment of HIV-positive individuals.

Decisions about when to start or switch a therapy often depend on the frequency with which individuals are monitored or tested. For example, the optimal time to switch antiretroviral therapy depends on the frequency with which HIV-positive individuals have HIV RNA measured. This paper describes an approach to use observational data for the comparison of joint monitoring and treatment strategies and applies the method to a clinically relevant question in HIV research: when can monitoring frequency be decreased and when should individuals switch from a first-line treatment regimen to a new regimen? We outline the target trial that would compare the dynamic strategies of interest and then describe how to emulate it using data from HIV-positive individuals included in the HIV-CAUSAL Collaboration and the Centers for AIDS Research Network of Integrated Clinical Systems. When, as in our example, few individuals follow the dynamic strategies of interest over long periods of follow-up, we describe how to leverage an additional assumption: no direct effect of monitoring on the outcome of interest. We compare our results with and without the "no direct effect" assumption. We found little differences on survival and AIDS-free survival between strategies where monitoring frequency was decreased at a CD4 threshold of 350 cells/µl compared with 500 cells/µl and where treatment was switched at an HIV-RNA threshold of 1000 copies/ml compared with 200 copies/ml. The "no direct effect" assumption resulted in efficiency improvements for the risk difference estimates ranging from an 7- to 53-fold increase in the effective sample size.

Rates and predictors of switching to tenofovir alafenamide-containing ART in a nationwide cohort.

BACKGROUND: Tenofovir alafenamide (TAF)-containing combinations were introduced in Switzerland after October 2016 and are recommended over tenofovir disoproxil fumarate (TDF) in patients with osteoporosis or impaired renal function. METHODS: We included all participants of the Swiss HIV Cohort Study on TDF-containing antiretroviral therapy with follow-up visits after January 2016. We determined the proportion of switches from TDF to TAF overall, and among patients with risk factors for TDF toxicity, including osteoporosis, impaired renal function or marked proteinuria. We used multivariable logistic regression to explore predictors of switching from TDF to TAF. RESULTS: We included 5'012 patients, of whom 652 (13.0%) had risk factors for TDF toxicity. A switch from TDF to TAF was undertaken in 2'796 (55.8%) individuals overall, and in 465 (71.3%) with risk factors. Predictors of switching to TAF were male sex (adjusted odds ratio 1.27, 95% confidence interval 1.07-1.50), age > 50 years (1.43, 1.23-1.66) and the presence of risk factors for TDF toxicity (2.21, 1.77-2.75). In contrast, patients with a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based single-pill regimen (0.11, 0.09-0.13), those treated in non-tertiary care centers (0.56, 0.46-0.70), as well as those with CD4 cell counts below 500/µL (0.77, 0.66-0.90) and with chronic hepatitis C infection (0.66, 0.54-0.80) were most likely to stay on TDF. CONCLUSIONS: Over 50% of patients on TDF-containing therapy, including the majority of patients at risk for TDF toxicity, were switched to TAF within two years of its introduction in Switzerland. Individuals on NNRTI-based single-pill regimens were most likely to remain on TDF.

Long-term Immune Response to Yellow Fever Vaccination in Human Immunodeficiency Virus (HIV)-Infected Individuals Depends on HIV RNA Suppression Status: Implications for Vaccination Schedule.

Background: In human immunodeficiency virus (HIV)-infected individuals, the immune response over time to yellow fever vaccination (YFV) and the necessity for booster vaccination are not well understood. Methods: We studied 247 participants of the Swiss HIV Cohort Study (SHCS) with a first YFV after HIV diagnosis and determined their immune responses at 1 year, 5 years, and 10 years postvaccination by yellow fever plaque reduction neutralization titers (PRNTs) in stored blood samples. A PRNT of 1:≥10 was regarded as reactive and protective. Predictors of vaccination response were analyzed with Poisson regression. Results: At vaccination, 82% of the vaccinees were taking combination antiretroviral therapy (cART), 83% had suppressed HIV RNA levels (<400 copies/mL), and their median CD4 T-cell count was 536 cells/µL. PRNT was reactive in 46% (95% confidence interval [CI], 38%-53%) before, 95% (95% CI, 91%-98%) within 1 year, 86% (95% CI, 79%-92%) at 5 years, and 75% (95% CI, 62%-85%) at 10 years postvaccination. In those with suppressed plasma HIV RNA at YFV, the proportion with reactive PRNTs remained high: 99% (95% CI, 95%-99.8%) within 1 year, 99% (95% CI, 92%-100%) at 5 years, and 100% (95% CI, 86%-100%) at 10 years. Conclusions: HIV-infected patients' long-term immune response up to 10 years to YFV is primarily dependent on the control of HIV replication at the time of vaccination. For those on successful cART, immune response up to 10 years is comparable to that of non-HIV-infected adults. We recommend a single YFV booster after 10 years for patients vaccinated on successful cART, whereas those vaccinated with uncontrolled HIV RNA may need an early booster.

Hepatitis delta-associated mortality in HIV/HBV-coinfected patients.

BACKGROUND & AIMS: Hepatitis delta virus (HDV) infection accelerates the progression of hepatitis B virus (HBV)-related liver disease. We assessed the epidemiological characteristics of HDV infection in the nationwide Swiss HIV Cohort Study and evaluated its impact on clinical outcomes. METHODS: All HIV-infected patients with a positive hepatitis B surface antigen test were considered and tested for anti-HDV antibodies. HDV amplification and sequencing were performed in anti-HDV-positive patients. Demographic and clinical characteristics at initiation of antiretroviral therapy, as well as causes of death were compared between HDV-positive and HDV-negative individuals using descriptive statistics. Kaplan-Meier and multivariable Cox regression analyses were used to evaluate the association between HDV infection and overall mortality, liver-related mortality as well as incidence of hepatocellular carcinoma (HCC). RESULTS: Of 818 patients with a positive hepatitis B surface antigen tests, 771 (94%) had a stored serum sample available and were included. The prevalence of HDV infection was 15.4% (119/771, 95% CI: 12.9-18.0) and the proportion of HDV-positive patients with HDV replication 62.9% (73/116). HDV-infected patients were more likely to be persons who inject drugs (60.6% vs. 9.1%) and to have a positive hepatitis C virus (HCV) serology (73.1% vs. 17.8%) compared to HDV-uninfected ones. HDV infection was strongly associated with overall death (adjusted hazard ratio 2.33, 95% CI 1.41-3.84), liver-related death (7.71, 3.13-18.97) and with the occurrence of HCC (9.30, 3.03-28.61). Results were similar when persons who inject drugs or HCV-coinfected patients were excluded from the analyses. CONCLUSIONS: The prevalence of HDV in hepatitis B surface antigen-positive patients in the Swiss HIV Cohort Study (SHCS) is high and HDV infection is independently associated with mortality and liver-related events, including HCC. LAY SUMMARY: Hepatitis delta virus (HDV) infection accelerates the progression of hepatitis B virus (HBV)-related liver disease. In a nationwide cohort of HIV-infected individuals in Switzerland, 15% of HBV-coinfected patients had antibodies to HDV infection, of which a majority had active HDV replication. HDV-infected individuals were 2.5 times more likely to die, eight times more likely to die from a liver-related cause and nine times more likely to develop liver cancer compared to HDV-uninfected ones. Our results emphasize the need for prevention programs (including HBV vaccination), the systematic screening of at risk populations as well as close monitoring, and underline the importance of developing new treatments for chronic HDV infection.